1. Field of the Invention
This invention relates to certain N-alkylaminofluorenecarboxamides and pharmaceutical compositions containing them. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases. The use of the compounds of this invention to the treatment of these disorders is indicated by the ability of the compounds to bind selectively to dopamnine receptor subtypes.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D.sub.2 receptors in the striatal region of the brain. The dopamine D.sub.3 receptor subtype has recently been identified (Sokoloff, P. et al., Nature 1990, 347, 146). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D.sub.3 receptor may play a major role in the etiology of schizophrenia. Selective D.sub.3 antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds of the present invention demonstrate high affinity and selectivity in binding to the D.sub.3 receptor subtype. They may be of potential use in treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias may also be treated directly or indirectly by modulation of D.sub.3 receptors.
Furthermore, compounds of this invention may be useful in treatment of depression, memory-impairment or Alzheimer's disease by modulation of D.sub.3 receptors which selectively exist in limbic area known to control emotion and cognitive functions. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse (Caine, S. B. and Koob, G. F.; Modulation of Cocaine Self Administration in the Rat through D-3 Dopamine Receptors. Science 1993, 260, 1814) and obsessive compulsive disorder (Goodman, W. K. et al., The Role of Serotonin and Dopamine in the Pathophysiology of Obsessive Compulsive Disorder. Clin. Psychopharmacol. 1992, 7, 35). The interaction of N-alkylaminofluorenecarboxamides with dopamine receptor subtypes is described. This interaction results in the pharmacological activities of these compounds.
U.S. Pat. No. 5,395,835 May 24, 1994 discloses N-aminoalkyl-2-napthamides which have affinity at dopamine D.sub.3 receptors. The novel compounds of claim 1 of the present invention differ significantly from this prior art in that they possess a fluorenecarboxamide substructure.
Murray, P. J. et al. (A Novel Series of Arylpiperazines with High Affinity and Selectivity for the Dopamine D.sub.3 Receptor. Bioorg. Med. Chem. Let. 1995, 5, 219) described 4-carboxamidobiphenyls which have affinity at dopamine D.sub.3 receptors. The novel compounds of the present invention differ significantly from this prior art in that the two aromatic rings of the aromatic carboxamide are fused at the ortho position to create a tricyclic ring system.